Shane Crotty

"There are no child prodigies in biology. Future physicists may play with radios or electronics, forcing electrons to flow along wire paths through light bulbs or amplifiers, but there is no comparable pastime for biologists. Nature-watching is no substitute. Simply looking at frogs is no more instructive than looking at a radio: the tinkering is is the important component. Perhaps someday, when molecular biology has reached elementary and secondary schools, promising young biologists will play with molecular biology sets the way chemists and physicists play with chemistry sets and circuit boards. As it is, most young biologists do no experiments before college. Of the few who do, almost all experiment with chemistry sets, only to switch to biology in college when they learn about its experimental possibilities."

"T cell help to B cells is a fundamental aspect of adaptive immunity and the generation of immunological memory. Follicular helper CD4 T (TFH) cells are the specialized providers of B cell help. TFH cells depend on expression of the master regulator transcription factor Bcl6. Distinguishing features of TFH cells are the expression of CXCR5, PD-1, SAP (SH2D1A), IL-21, and ICOS, among other molecules, and the absence of Blimp-1 (prdm1). TFH cells are important for the formation of germinal centers. Once germinal centers are formed, TFH cells are needed to maintain them and to regulate germinal center B cell differentiation into plasma cells and memory B cells. This review covers TFH differentiation, TFH functions, and human TFH cells, discussing recent progress and areas of uncertainty or disagreement in the literature, and it debates the developmental relationship between TFH cells and other CD4 T cell subsets (Th1, Th2, Th17, iTreg)."

"Tfh cell differentiation is a multistage, multifactorial process. There is no single event that defines Tfh cell differentiation, unlike T helper 1 (Th1) cell differentiation, for instance, which can be fully induced by interleukin-12 (IL-12) exposure in vitro or in vivo. Instead, Tfh cell differentiation is a multistep, multisignal process that also accommodates a significant amount of heterogeneity."

"‘Help’ to B cells is not a single product of TFH cells and not even a single process. T cell help to B cells can be divided into seven distinct functions, ... : proliferation, survival, plasma cell differentiation, somatic hypermutation, class-switch recombination, adhesion and attraction. These seven different forms of help are all contributors to TFH cell–B cell interactions, and each process consists of multiple pathways ... Furthermore, some molecules have a role in several different forms of help."

"Although T cell help to B cells was one of the very first defined functions of T cells (Crotty, 2015), the identification of the CD4+ T cell subset responsible for T cell-dependent humoral immune responses developed much later. The term T follicular helper (Tfh) cell was coined in a series of studies on human tonsillar germinal center (GC) CD4+ T cells and CXCR5+ CD4+ T cells in blood (Crotty, 2011). Early converts rightly point to those papers as seminal for establishing the field, but it was not until Bcl6 was determined to be a lineage-defining transcription factor (TF) of Tfh cells that Tfh cells were broadly accepted among immunologists as a distinct lineage of helper CD4+ T cells and required for GCs. That trifecta of papers was published 10 years ago (Johnston et al., 2009, Nurieva et al., 2009, Yu et al., 2009), including the demonstration that the TFs Blimp1 and Bcl6 are potent reciprocal antagonists (Johnston et al., 2009) …"